Mesenchymal stem/stromal cells to enhance cytotoxic T cell immunity during HIV infection

间充质干细胞/基质细胞增强 HIV 感染期间的细胞毒性 T 细胞免疫

• 批准号: 10592965
• 负责人: Amir Kol
• 金额: $ 31.94万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592965
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Allogenic; Animals; Autopsy; B-Lymphocytes; BLR1 gene; Biological Assay; Blood; CD8-Positive T-Lymphocytes; Chronic; Clinical Trials; Color; Complex; Confocal Microscopy; Cytotoxic T-Lymphocytes; Data; Development; Epigenetic Process; Exclusion; Flow Cytometry; Foundations; Functional disorder; Genetic Transcription; Goals; Granzyme; HIV; HIV Infections; HIV/AIDS; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immunity; Immunohistochemistry; In Situ; In Vitro; Infiltration; Infusion procedures; Interruption; Intestinal Mucosa; Intravenous infusion procedures; Knowledge; Location; Lymphoid Follicle; Macaca; Macaca mulatta; Malignant Neoplasms; Mesenchymal; Microanatomy; Mission; Modeling; Molecular; Pathogenesis; Patients; Peripheral; Phenotype; Population; Process; Production; Property; Public Health; Rejuvenation; Research; Research Project Grants; Role; SIV; Safety; Sampling; Scientist; Site; Solid; Sorting; Stains; Stromal Cells; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Tissues; Translational Research; Veterinarians; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Latency; Virus Replication; antiretroviral therapy; cell killing; cytokine; exhaust; exhaustion; global health; immune cell infiltrate; immunoregulation; improved; innovation; lymph nodes; molecular marker; nonhuman primate; novel; novel therapeutics; peripheral blood; pre-clinical; programs; receptor; response; single-cell RNA sequencing; stem; therapeutic candidate; therapeutic target; trafficking; viral rebound

Multipotent stem/stromal cells (MSC) are promising candidate therapeutics for HIV infection, given their potent immunomodulatory properties and wide safety margins. It remains unknown if MSC can reverse CD8 T cell exhaustion and promote trafficking of CD8 T cells into privileged sites during chronic HIV infection. Thus, there is a critical need to determine whether CD8 T cell exhaustion can be therapeutically targeted by MSC. Our long-term goal is to define mechanisms of MSC-induced immune-modulation during chronic viral infections so that improved therapeutic strategies be developed. Our overall objective in this application is to determine if MSC treatment can enhance viral clearance via reversal of exhausted CD8 T cells in chronic SIV-infected macaques. Our central hypothesis is that systemic infusions of allogeneic MSC enhance viral clearance in ART-naïve, and delay viral rebound upon ART interruption in ART-treated SIV-infected macaques, via reversal of CD8 T cell exhaustion and infiltration of privileged sites. The rationale that underlies the proposed research is that CD8 T cell exhaustion and viral sequestration are major mechanisms of HIV viral persistence that may be targeted with MSC treatment. To test our hypothesis we will use the SIV-infected non-human primate model of AIDS. SIV-infected animals will be treated with a combination of ART and/or MSC and samples from peripheral blood, gut tissue, and lymph nodes will be collected during necropsies. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the impact of MSC treatment on exhausted CD8 T cell populations in rhesus macaques chronically infected with SIV. Our working hypothesis is that MSC treatment reverses CD8 T cell exhaustion that is driven by chronic SIV infection. We will sort CD8 T cells from blood, gut tissue, and lymph nodes and perform single-cell RNAseq analysis, multi-color flow cytometry, and ex-vivo stimulation assays. 2) Determine the impact of MSC treatment on CD8 T cell trafficking into lymphoid follicles in rhesus macaques chronically infected with SIV. Our working hypothesis is that MSC treatment in chronic SIV-infected macaques enhances CXCR5+/CD8 T cell trafficking into B-cell follicles. We will determine the micro-anatomical distribution and phenotype of SIV-specific CD8 T cells and viral reservoirs in gut tissue and lymph nodes via in situ MHC-tetramer, and immunohistochemistry staining, and confocal microscopy. The research proposed in the application is innovative because it explores a new therapeutic paradigm of targeting multiple mechanisms of HIV persistence concurrently on multiple mechanistic levels. The proposed research is significant because HIV/AIDS remains a significant global health crisis that is partially driven by viral persistence despite effective antiretroviral therapy and suppression of viral replication. Moreover, as CD8 T cell exhaustion has been implicated in the pathogenesis of multiple other chronic viral diseases and malignancies, findings stemming from this study have the potential to impact broadly and deeply. Findings from this study are directly translatable as MSC are readily available for clinical trials.

多能干/基质细胞（MSC）是有希望的候选治疗HIV感染的药物，因为它们的有效性。 免疫调节特性和广泛的安全范围。目前尚不清楚MSC是否可以逆转CD 8 T细胞 在慢性HIV感染期间，CD 8 T细胞耗竭并促进其向特权部位的运输。因此 是确定CD 8 T细胞耗竭是否可以被MSC治疗靶向的关键需求。我们 长期目标是确定慢性病毒感染期间MSC诱导的免疫调节机制， 开发出更好的治疗策略本申请的总体目标是确定 MSC治疗可以通过逆转慢性SIV感染者中耗尽的CD 8 T细胞来增强病毒清除 猕猴我们的中心假设是，全身输注同种异体MSC可以增强病毒清除， ART初治，并通过逆转延缓ART治疗的SIV感染猕猴中ART中断后的病毒反弹 CD 8 T细胞耗竭和特殊部位浸润的风险。拟议研究的基本原理 CD 8 T细胞耗竭和病毒隔离是HIV病毒持续存在的主要机制， 针对MSC治疗。为了验证我们的假设，我们将使用SIV感染的非人灵长类动物模型 艾滋病SIV感染的动物将用ART和/或MSC和来自AIV的样品的组合治疗。 在尸检期间收集外周血、肠组织和淋巴结。核心假设将 通过追求两个具体目标进行测试：1）确定MSC处理对耗尽的CD 8 T细胞的影响 恒河猴慢性感染SIV。我们的工作假设是MSC治疗 逆转由慢性SIV感染驱动的CD 8 T细胞耗竭。我们将从血液、肠道中分离CD 8 T细胞 组织和淋巴结，并进行单细胞RNAseq分析、多色流式细胞术和离体 刺激测定。2)确定MSC处理对CD 8 T细胞运输到淋巴滤泡中的影响 在慢性感染SIV的恒河猴中。我们的工作假设是，MSC治疗慢性 SIV感染的猕猴增强CXCR 5 +/CD 8 T细胞运输到B细胞卵泡中康贝特人将以 肠道组织中SIV特异性CD 8 T细胞和病毒储库的显微解剖学分布和表型， 淋巴结通过原位MHC-四聚体，免疫组织化学染色，共聚焦显微镜。的 申请中提出的研究是创新的，因为它探索了一种新的靶向治疗模式， 艾滋病毒持续存在的多种机制同时在多个机制水平上。拟议的研究是 这是因为艾滋病毒/艾滋病仍然是一个严重的全球健康危机，部分原因是病毒感染。 尽管有有效的抗逆转录病毒治疗和抑制病毒复制，但仍持续存在。此外，作为CD 8 T细胞 衰竭与多种其它慢性病毒性疾病和恶性肿瘤的发病机制有关， 这项研究的结果有可能产生广泛和深刻的影响。这项研究的结果是 可直接翻译为MSC的MSC可容易地用于临床试验。